Chemical synthesis of polyamides is well-known in the art. However, chemical synthesis often has many undesirable characteristics including 1) the use of expensive or toxic chemical catalysts and reactants, 2) the production of excess waste, especially for processes requiring high dilutions with solvents, and 3) a lack of selectively necessary to produce the desired products in high purity.
Enzymatic synthesis of polyesters and polyamides has been demonstrated using a variety of hydrolytic enzymes (i.e., lipases, esterases, etc.). Enzymes and their typical substrates are nontoxic, and enzymatic processes usually offer higher selectivity, decreased waste generation, and faster catalytic rates under milder conditions when compared to traditional chemical synthesis. In particular, lipases (E.C. 3.1.1.3) have been used extensively for the synthesis of polyesters and/or polyester (amides) in the presence or absence of organic solvents (Chaudary et al., Biotech Prog. 13:318-325 (1997); Brazwell et al., J. Polym. Sci. Part A: Polym Chem. 33:89-95 (1995); Binns et al., J. Chem. Soc. Perkin Trans. 1:899-904 (1993); Geresh et al., Biotech. Bioeng., 37:883-888 (1991); and WO 94/12652).
Chemical and/or enzymatic polymer synthesis typically results in the production of linear oligomers that can be used for traditional in-mold polymerization (i.e., reaction injection molding) for the formation of shaped products. However, in-mold polymerization using linear (polyester or polyamide) oligomers has some limitations. Upon in-mold polymerization, the end groups on the linear oligomers will produce unwanted byproducts during the reaction such as water (i.e., when reacting a carboxylic acid end group with a hydroxyl or amine end group) or organic alcohols such as methanol (i.e., when reacting an ester with a hydroxyl or amine end group). The unwanted byproducts typically need to be removed and may adversely affect the physical characteristics of the molded product. These adverse effects include increased void content and decreased surface finish quality. Lastly, linear oligomers tend to have high melt viscosities, which may limit the ability to form higher molecular weight polymers or may limit their use in the formation of finer moldable products.
Cyclic ester oligomers (CEOs) and cyclic amide oligomers (CAOs) offer a distinct processing advantage over the use of linear oligomers. First, cyclic oligomers do not introduce endgroups during polymerization. This allows materials to be prepared without the formation of volatiles in the in-mold polymerization process. Second, much higher molecular weight polymers can be prepared because the monomers lack end groups, which translates into polymers without many end groups. Third, cyclic oligomers typically have lower melt viscosities. The use of lower melt viscosity cyclic oligomer for in-mold polymerization (e.g., reaction injection molding) enables production of polymers having molecular weights typically not obtainable when using linear oligomers and allows formation of finer moldable parts.
Cyclic ester oligomers (CEOs) have been known for many years, see for instance U.S. Pat. No. 2,020,298. CEOs are known to be present in varying, usually small, quantities in many linear polyesters and have been isolated from such linear polyesters. They are often low viscosity liquids that may be polymerized to higher molecular weight linear polyesters by ring opening polymerization, see for instance U.S. Pat. Nos. 5,466,744 and 5,661,214 and references cited therein. Enzymatic synthesis of CEOs has previously been reported (U.S. Ser. No. 10/698,275, hereby incorporated by reference; Lavalette et al., Biomacromolecules, 3:225-228 (2002)).
Cyclic amide oligomers (CAOs) are normally produced during chemical polycondensation reactions. Kricheldorf et al. (Macromolecules, 34:8879-8885 (2001)) produced a variety of aliphatic and aromatic linear amide oligomers (LAOs) and CAOs by the chemical reaction of diamines or silylated diamines with dicarboxylic acid dichlorides. Kricheldorf et al. do not teach an enzymatic method for the production of cyclic amide oligomers.
WO 94/12652 describes a process for the production of polyesters or polyester (amides) in an enzyme-catalyzed reaction in the absence of added solvent, whereby the desired polyesters or polyesteramides are produced with high average molecular weight and narrow dispersity. For the production of polyester (amides), the reaction of at least one aliphatic dicarboxylic acid or derivative thereof with at least one aliphatic hydroxyamine, diol, polyol, diamine or polyamine, and optionally, at least one aliphatic hydroxycarboxylic acid, aminocarboxylic acid or derivative is described. The polyester or polyester (amide)s produced in this process have a most preferred acid number of about 1 (page 18, line 17), indicating that the products are linear polyester or polyester (amide) oligomers, and not cyclic polyester or polyester (amide) oligomers. In the case of polyester production, the production of up to 1.5% cyclic diester impurity is indicated as undesirable, and methods are provided for the removal of unwanted cyclic impurity (page 19, lines 1-15).
Recently, it has been reported that linear amide oligomers (LAOs) can be made from diesters and diamines using hydrolytic enzymes (e.g. lipases, esterases, proteases, etc.). Cheng et al. (U.S. Pat. No. 6,677,427) report an enzyme catalyzed process to prepare a variety of linear and/or branched polyamide oligomers by the reaction of a polyamine and diester in the presence of a hydrolytic enzyme obtained from species such as Candida (Candida antartica), Pseudomonas species (Pseudomonas fluorescens), or Mucor species (Mucor miehei). Cheng et al. do not report the formation of cyclic amide oligomers. Specifically, Cheng et al. state in column 13, lines 2-4, “Although the polyamides may be linear or branched, the polyamides of the present invention are preferably linear and have a narrow molecular weight polydispersity (Mw/Mn)”, and in column 6, lines 20-21, “The polyamides of the present invention may have residues of at least one diester and at least one polyamine”. The polyamides described in Cheng et al. generally have a molecular weight range from about 4,000 to 12,000 Daltons (column 6, line 29), indicating that high molecular weight linear polyamides were formed. The process of Cheng et al. was performed without added solvent, or optionally in the presence of at least one protic solvent such as methanol, ethanol, ethylene glycol, glycerol, t-butanol, isopropanol, or in a water/salt mixture such as water/NaCl (column 4, lines 26-31); preferably, the reaction was performed in the absence of solvent (column 8, lines 37-39; column 10, lines 52-57; Example 1, lines 17-19; Examples 3-5). All of the working examples were conducted in the absence of solvent at essentially equimolar amounts of the diester and polyamine, where the concentration of each substrate was in excess of about 2.75 molar. Completion of each reaction was generally determined by the formation and characterization of a solid product.
Gutman et al. (Tetrahedron Lett., 33(27):3943-3946 (1992)) describe the use of porcine pancreatic lipase to catalyze the formation of macrocyclic bislactams from diesters and diamines and found that no reaction occurs in the absence of enzyme, and that in the presence of enzyme the reaction proceeds only when employing the activated monochloroethyl diester, but not with the ethyl diester or the free dicarboxylic acid (p 3944, last paragraph). Gutman et al. teaches that the enzymatic production of macrocyclic bislactams requires that the alkoxy leaving group of the diester be activated (e.g. 2-chloroethyoxy), whereas in the present invention the diesters employed in the production of cyclic amide oligomers (CAOs) can have unactivated alkoxy leaving groups (e.g., methoxy, ethoxy).
The problem to be solved is to provide a method for the enzymatic synthesis of cyclic amide oligomers from non-activated diesters and diamines.